568 Send Orders for Reprints to reprints@benthamscience.

ae

Current Organic Synthesis, 2017, 14, 568-571

REVIEW ARTICLE
ISSN: 1570-1794 Volume 14, Number 4
eISSN: 1875-6271

Current
Organic Synthesis

Applications of Michael Addition Reaction in Organic Synthesis Impact

Factor:
2.05

BENTHAM
SCIENCE

Gangliang Huang* and Xue Li

Chongqing Key Laboratory of Green Synthesis and Applications, College of Chemistry, Chongqing Normal University, Chongqing,
401331, China

ARTICLE HISTORY
Received: July 30, 2016
Revised: November 07, 2016
Accepted: November 08, 2016
DOI:
10.2174/1570179414666161121124
846
Abstract: Michael addition reaction has been a very classical reaction in the field of organic synthesis. It is
widely used to synthesize all kinds of natural products and drugs. Since the beginning of 21st century, people's
environmental awareness has been enhanced and the research on green chemistry has been advanced. The Mi-
chael addition method with high efficiency, simplicity and greenness has been the goal pursued by organic chem-
ists. Herein, the concepts and mechanisms of Michael addition reaction were discussed, and the applications of
Michael addition reaction in the synthesis of natural products and complex compounds with biological activities
were summed up.

Keywords: Michael addition reaction, type, organic synthesis, applications.

1. INTRODUCTION Okamura et al. [2] reported an asymmetric oxy-Michael addi-

Michael addition reaction is also called Michael condensation
reaction. The combination of aldol condensation reaction and Mi-
chael addition reaction is an important way to parallel a hexatomic
ring with another hexatomic ring, which is known as Robinson
annulation. In addition, it is also an important method for the syn-
Current Organic Synthesis
tion for the synthesis of a -hydroxy-,-unsaturated thioester via
hemiacetal intermediates by using the Cinchona-alkaloid-thiourea-
based bifunctional organocatalysts.
Kobayashi et al. [3] developed an unprecedented enantioselec-
tive intramolecular oxa-Michael reaction of unactivated ,-

thesis of 1,5-dicarbonyl compounds. Michael addition reaction can unsaturated amides and esters by using a powerful hydrogen-bond-
also be used in the introduction of angular methyl on the two car- donating organocatalyst.
bon atoms fused. Many drugs possess the structure of angular
methyl that is hard to introduce with other ways. Moreover, many 2.2. Michael Addition Reaction of Carbanion
substances that are difficult to be synthesized by conventional
First, the active hydrogen on carbon is captured to form a car-
methods can be successfully synthesized by Michael addition reac-
banion, Then, the 1,4-conjugate addition occurs with carbanion and
tion.

H
R2 O R O RO-
O + O
Base H
R-O-H R-O- +
1 Base-H 2 R1 OR R2 R1 OR R2 R1 OR
3 4 5
Fig. (1). The oxa-Michael addition reaction.

2. MICHAEL-TYPE ADDITION REACTIONS
2.1. The oxa-Michael Addition Reaction
The Michael addition reaction, which uses the oxygen negative
ion as donor to finally form the carbon oxygen bond, is called the
oxa-Michael addition reaction. The reaction mechanism [1] is
shown in Fig. (1). First, alcohol loses the proton under the action of
base to form alkoxide anion, which then attacks the receptor to
finally get the addition product. Michael addition reaction mecha-
nism with oxygen is similar to other heteroatoms, such as nitrogen,
and so on. Moreover, additional compound 4 can also be used as a
new nucleophile to carry out Michael addition reaction again.
*Address correspondence to this author at the Chongqing Key Laboratory of Green
Synthesis and Applications, College of Chemistry, Chongqing Normal University,
Chongqing, 401331, China; Tel: (86)013068336573; Fax: (86)013068336573;
E-mail: huangdoctor226@163.com
1875-6271/17 $58.00+.00
receptor, the formed addition product captures a proton from the
solvent to form enol. Finally, the tautomerism occurs to form the
final product.
2.3. Double Michael Addition Reaction
Continuous two Michael addition reactions are called the dou-
ble Michael addition reactions. First, the oxygen atom in compound
7 is complexed with the acid. So, compounds 6 and 7 can better
carry out Michael addition reaction to get compound 8. Then, com-
pound 8 undergoes Michael addition reaction in the molecule again
to obtain compound 9 (Fig. 2) [4].
Meninno et al. [5] reported a cascade double Michael reaction
for the stereoselective synthesis of highly functionalized
tetrahydrothiophenes by reacting between trans--cyano-,-
unsaturated ketones and trans-tert-butyl 4-mercapto-2-butenoate
with a readily available amine thiourea. The products were pro-
vided in high yields, good diastereoselectivity and excellent
enantioselectivity.
© 2017 Bentham Science Publishers
Applications of Michael Addition Reaction
TBSO
+ Tf2NH
O 9
6 7
Fig. (2). Double Michael addition reaction.
3. APPLICATIONS OF MICHAEL ADDITION REACTION
IN ORGANIC SYNTHESIS
3.1. Synthesis of 1,4-Diketone
It is an effective method that the ,-unsaturated nitro com-
pounds and silyl enol ethers carry out Michael addition reaction for
the synthesis of 1,4-diketones, which are further cyclized to obtain
cyclopentenones.
3.2. Robinson Annulation
Robinson annulation is a reaction that is the combination of al-
dol condensation and Miehael addition reaction. For example, the
enolate ion of cyclic ketone and 3-butylene-2-one first carry out the
Michael addition reaction, and then the intramolecular aldol con-
densation occurs. The angular methyl is introduced into the final
product, and the angular methyl group is a special structural unit
that exists in many natural products. The raw material used for the
reaction can be prepared by Mannich reaction, and then can be di-
rectly used in the Michael addition reaction.
3.3. Enamine-Michael Reaction
In polar solvents, the reaction of enamine and Michael receptor
is in the opposite position. In general, the asymmetric ketones carry
out Michael reaction under the action of base, manily taking place
on -carbon that is more substituted. But it is opposite to enamine-
Michael reaction, which occurs in place of less substituted carbon.
As N- alkylation is reversible in the reaction, it can generally get
very good yield of C- alkylation product. Therefore, we can use this
point in organic synthesis. First, the asymmetric ketone is converted
into enamine, then the Mihcael reaction occurs, and then the
method of hydrolysis is used to control the localization, finally
synthesize the desired product.
3.4. Synthesis of 1,5-Dicarbonyl Compounds
The Michael addition reaction can be used for the synthesis of
1,5-dicarbonyl compounds. The 1,5-dicarbonyl compounds can be
cut off in two different places. So, it should be compared to choose
a more reasonable way to cut off. On the one hand, the used silyl
enol ethers can react with a variety of ,-unsaturated carbonyl
compounds to prepare the 1,5-dicarbonyl compounds. On the other
hand, the reaction conditions are also quite mild and better than the
base-promoted Michael reaction.
4. APPLICATION EXAMPLES OF MICHAEL ADDITION
REACTION
4.1. Applications of Michael Addition Reaction in Drug
Synthesis
Fredericamycin A is a kind of antitumor antibiotics, which is
the only one isolated from the gray Streptomyces. It has a good anti-
cancer activity and cytotoxic activity in vitro.
Boger's group [6] used Dieckmann condensation reaction and
Michael addition reaction to construct the DEF-ring structure of
above molecule. The cyclopentenone as Michael addition receptor
Current Organic Synthesis, 2017, Vol. 14, No. 4 569
TBSO
O
Tf2NH
H
TBSO O
8
was mixed with multi-substituted 4-picoline treated with an excess
of LDA to get the corresponding compound, and after the in-
tramolecular acylation, the needed DEF-ring compound was ob-
tained. And this important intermediate (DEF-ring compound) was
the basis for the completion of total synthesis.
In addition, there were also many researchers to use this reac-
tion to efficiently construct the AB-ring structure in the total syn-
thesis of Forskolin. For example, Li et al. [7] reported that 3-
hydroxyl cyclocitral and diketene were reacted to obtain the corre-
sponding intermediate, and AB-ring compound could be obtained
by the Michael addition and aldol condensation. This was a simple
method for the synthesis of Forskolin A, B ring, and the total yield
reached 40.8%. Koft et al. [8] also studied and published a similar
route, which obtained the AB-ring skeleton compound 20 with 5,6-
double bond mainly by the Michael addition. The Leclaire's group
[9] also conducted a thorough study of the reaction. Qiu's group
[10] used the same route for constructing the Ziegler intermediate,
which was the key intermediate of Forskolin. Corey [11] is a fa-
mous organic chemist, and the Nobel prize winner. The same reac-
tion was also used when he constructed the vinyl side chain of
molecule.
Hack et al. [12] developed a highly stereoselective one-pot pro-
cedure to synthesize the five-membered annulated hydroxycoumar-
ins. They used a Michael addition/hydroalkoxylation reaction to
obtain a series of functionalized coumarin derivatives in good
yields and good to excellent enantioselectivities by merging pri-
mary amine catalysis with silver catalysis.
4.2. The Application of Michael Addition in the Synthesis of
Quinone Compounds
Natural naphthoquinone compounds are the material basis for
new insecticide development. They have diverse biological activi-
ties and some naphthalenones have strong snail-destroying activity.
For example, naphthoquinone lapachol can be separated from the
sikkmensis tree plant. The antimalarial agents (naphthalenone de-
rivatives) against Plasmodium falciparum extracted from certain
chandelier tree plant also have significant anti-trypanosomal activ-
ity. Because the naphthalenones have the significantly biological
activities, their total synthesis has attracted wide attention of chem-
ists. For example, the naphthoquinone compounds against malaria
were successfully synthesized by applying bionics.
Studies have shown that these compounds have strong biologi-
cal activities, and it is also the presence of quinone pharmacophore
in the molecule. The 2-hydroxyl naphthoquinone derivatives as a
kind of important pigment exist in many kinds of naphthoquinone
compounds, and they have strong biological activities. For example,
atorvastatin is a very important carbon alkylated hydroxyl naphtho-
quinone compound, it has antioxidant, anti-malaria, antibacterial,
insecticidal, anti-cone worm and can enhance the immune function
and other functions. At present, many ketones have been developed
to be used in medicines, such as anticancer drugs mitoxantrone and
doxorubicin have been widely used clinically; the anti-leukemia,
anti-lymphoma and other aspects show good activities. Naphtho-
quinone compounds can also be used as dyes in the industrial fields.
570 Current Organic Synthesis, 2017, Vol. 14, No. 4
Due to the unique biological activities of quinone compounds in
medicinal chemistry, chemists and pharmaceutical scientists are
aiming to better investigate the pharmacological properties of qui-
none compounds and develop them as novel bioactive reagents.
Therefore, chemical synthesis of quinone compounds has also been
put on the agenda. And the synthesis of these final compounds is
also inseparable from Michael addition reaction.
4.3. Application of oxa-Michael Addition Reaction in Total
Synthesis
4.3.1. Total Synthesis of Forskolin
Forskolin, a diterpene compound, was separated from the Co-
leus forskohlii flower of India Labiatae plant. It has strong antitu-
mor metastasis, anti-glaucoma, the treatment of congestive heart
failure, activation of adenosine cyclase, anti-bronchial asthma and
other pharmacological activities.
Forskolin has 20 carbon atoms, having 8 chiral carbons. It can
lead the interest to many world's organic chemists and drug
scientists because of the challenge for total synthesis of its complex
structure and useful biological activities. The C ring in its structure
is a pyran ring structure, and many chemists have used oxa-Michael
addition reaction to synthesize the C ring. The structure of
Forskolin C ring was constructed by the intramolecular oxa-
Michael addition under the action of Ziegler [13] compound in the
methanol solution of potassium methoxide. Ikegami's group [14]
constructed the C ring by using the same method.
4.3.2. Total Synthesis of (+)-Calanolide A
(+)-Calanolide A [15] is a promising drug for the treatment of
AIDS, and it has been used in clinical applications in the United
States. It is a kind of natural organic compound extracted from
Calophyllum lanigerum, and the intramolecular D-ring structure is
considered to be the key to the anti HIV-1 activity. The Ishikawa's
group [16] also used the (-)-quinine to catalyze the intramolecular
oxa-Michael addition reaction in the asymmetric synthesis of D
ring.
The group used several different routes for the synthesis of tar-
get molecule, but they were mostly based on the oxa-Michael addi-
tion.
4.3.3. Total Synthesis of Culeatins A and B
The natural products Culeatins A and B have the spiral struc-
ture, and the synthesis of spiral ring structure is very challenging.
The Chandrasekhar's group [17] also used the oxa-Michael addition
reaction for the total synthesis of Culeatins A and B, and the yields
were higher.
4.4. APPLICATION OF CONTINUOUS MICHAEL ADDI-
TION REACTION IN TOTAL SYNTHESIS
4.4.1. Total Synthesis of Culmorin
(-)-Culmorin has good antibacterial activity against various
fungi, and it was separated from the metabolites of Fusarium cul-
morum. Therefore, the total synthesis of (-)-Culmorin has a very
important significance.
Takasu's group [18] efficiently constructed the tricy-
clo[5.3.0.03,8] decane backbone, which was obtained with the cor-
responding compound by two Michael addition reactions, and its
total synthesis was further completed. The advantage of this method
is that it does not require few steps to protect and deprotect, the
tricyclic system of Culmorin can be obtained in only one step, and
the regioselectivity and stereoselectivity can be in very good con-
trol.
Huang and Li
4.4.2. Synthesis of Valeriananoids A, B, and C
Valeriananoids A, B, and C have the actions of calmness and
stopping spasm, and were extracted from the root of Valeriana
fauriei.
Hagiwara's group [19] used double Michael addition reactions
as the key reaction and efficiently completed the asymmetric syn-
thesis of Valeriananoids A, B, and C. After the group synthesized
the key intermediate, they finally completed the total synthesis of
Valeriananoid A in 34% of the total yield (using corresponding
compound as raw material to calculate), then it was easy to finish
the total synthesis of Valeriananoids B and C. So, we can see that
the asymmetric synthesis of double Michael addition reactions
plays a decisive role in the construction of double ring system.
4.4.3. The Total Synthesis of (-)-Epibatidine
Epibatidine is a kind of alkaloid. It was isolated from the skin
extracts of Epipedobates ericolord poison frog from Ecuador in
1992, by Daly et al. [20]. Natural Epibatidine is the left-hand enan-
tiomer, it has a strong analgesic activity, is about 200
500 times as
morphine, and there is a different mechanism for analgesic effect
with morphine and opium. Therefore, its synthesis is also very im-
portant.
Takemoto's group [21] used the nitroolefin and bifunctional
thiourea to catalyze the double Michael addition of ,-unsaturated
-ketoester, and this addition showed the stereoselectivity. Finally,
they finished the total synthesis of (-)-Epibatidine in a seven-step
reaction, and the total yield was found to be 30%.
Kayal and Mukherjee [22] developed the first organocatalytic
asymmetric Michael addition/cyclization cascade reaction of 3-
isothiocyanatooxindoles and nitro olefins by using a cinchonidine-
derived bifunctional catalyst. The resulting products were obtained
in high yields with good diastereo- and enantioselectivity.
4.5. Other Applications of Michael Addition Reaction
Huang et al. [23] used fluorous cinchona alkaloid to catalyze
the Michael addition reaction of -fluoro--ketoesters and
maleimides with high enantioselectivity and diastereoselectivity.
Muramulla et al. [24] used the modularly designed organocata-
lysts (MDOs) to catalyze the stereoselective Michael addition of
enolizable ketones and aldehydes to maleimides. The corresponding
Michael addition products, 3-substituted succinimides, could be
obtained in excellent yields and high enantio- and diastereoselectiv-
ity.
Tsakos et al. [25] reported the first organocatalytic asymmetric
domino Michael-Henry reaction between 1,4-cyclohexanedione and
nitroalkenes to obtain bicyclo[3.2.1]octane derivatives, which were
a single diastereoisomer with excellent enantioselectivities.
Oueis et al. [26] reported the irreversible Michael addition of
thiols to acrylamides as a new tool for the kinetic target-guided
synthesis. The potent and selective acetylcholinesterase inhibitors
were assembled by the enzyme in an unprecedented enzymatic
hydrolysis/thio-Michael addition procedure.
Chen and Pullarkat [27] developed a palladacycle-catalyzed
tandem Heck-intramolecular aza-Michael reaction for the one-pot
synthesis of 1-substituted isoindolines using N-unprotected 2-
bromobenzylamines and acrylates in high yields.
5. DEFICIENCIES AND IMPROVEMENT OF MICHAEL
ADDITION REACTION

The amount of alkali should be controlled for Michael addi-
tion reaction, and the general amount of alkali should be enough for
the amount of catalyst. If the reaction temperature is higher and the
time required is very long, a large amount of alkali used can cause
side effects. For example, 1,5-dicarbonyl compounds in excessive
Applications of Michael Addition Reaction
alkali (sodium alkoxide) produce Claisen condensation [28]. Ab-
normal yield will occur in case of using excess sodium alkoxide
catalyst in the Michael addition reaction.

Michael addition reaction is a reversible reaction, and it can
not only produce the raw material but also produce a complex mix-
ture. In addition to the original donor and receptor in the reaction
mixture, different substances exist which add to further complica-
tions, especially when the catalyst reaction is alkali-based.
 When there are many ,-unsaturated ketones as receptors in
Michael addition reaction, the self-condensation reaction (double
Michael addition reaction, a Michael addition reaction, and aldol
reaction) [29] also will occur if excess base is used. One of the
improved methods is to import the triethyl silyl group as a stable
group into the -position of ,-unsaturated ketone, and the self-
polymerization of ,-unsaturated ketone can be avoided. After the
Michael addition reaction is completed, the triethyl silyl group can
be removed by hydrolysis to obtain good yield [30].
From the above analysis, we can know that we perform the re-
action in the presence of proton solvents (such as water or alcohol),
so that further conversion of Michael adduct can be minimized. To
reduce the reverse Michael reaction and the dialkylation reaction,
excess active methylene compound and most mild reaction condi-
tions should be used which are pretty good to promote the occur-
rence of Michael reaction.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
The Project Sponsored by the Scientific Research Foundation
for the Returned Overseas Chinese Scholars, State Education Min-
istry. The work was also supported by Scientific and Technological
Research Program of Chongqing Municipal Education Commission
(Grant No. KJ1400523), Foundation Project of Chongqing Normal
University (No. 14XYY020), Chongqing Research Program of
Basic Research and Frontier Technology (No. cstc2015jcyj
A10054), Chongqing Postgraduate's Research and Innovation Pro-
ject (No. CYS15153), and Chongqing University Students' Training
Project of Innovation & Undertaking (No. 201610637076), China.
REFERENCES
[1] Carl, F.; Nising, S.B. The oxa-Michael reaction: from recent developments to
applications in natural product synthesis. Chem. Soc. Rev., 2008, 37(6),
1218-1228.
[2] Okamura, T.; Asano, K.; Matsubara, S. Organocatalytic asymmetric oxy-
Michael addition to a -hydroxy-,-unsaturated thioester via hemiacetal in-
termediates. Chem. Commun., 2012, 48, 5076-5078.
[3] Kobayashi, Y.; Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y. A
powerful hydrogen-bond-donating organocatalyst for the enantioselective in-
tramolecular oxa-michael reaction of ,-unsaturated amides and esters.
Angew. Chem. Int. Edit., 2013, 52(42), 11114-11118.
[4] Jung, M.E.; Ho, D.G. Stepwise acid-promoted double-Michael process: An
alternative to Diels-Alder cycloadditions for hindered silyloxydiene-
dienophile pairs. Org. Lett., 2007, 9(2), 375-378.
[5] Meninno, S.; Croce, G.; Lattanzi, A. Asymmetric synthesis of trisubstituted
tetrahydrothiophenes bearing a quaternary stereocenter via double Michael
Current Organic Synthesis, 2017, Vol. 14, No. 4 571
reaction involving dynamic kinetic resolution. Org. Lett., 2013, 15(13),
3436-3439.
[6] Boger, D.L.; Hueter, O.; Mbiya, K.; Zhang, M. Total synthesis of natural and
ent-fredericamycin A. J. Am. Chem. Soc., 1995, 117(48), 11839-11849.
[7] Li, T.T.; Wu, Y.L. An approach to forskolin an efficient synthesis of a tri-
cyclic lactone intermediate. Tetrahedron Lett., 1988, 29(33), 4039-4040.
[8] Emil, R.K.; Atul, S.K.; Thomas A.B. Synthesis of a potential forskolin A-B
ring precursor by tandem Michael-Aldol reactions. Tetrahedron Lett., 1987,
28(25), 2799-2800.
[9] Leclaire, M.; Levetet, R. A simple access to a forskoli nprecursor. Synth.
Commun., 1993, 23(13), 1923-1927.
[10] Ye, H.; Deng, G.; Liu, J.; Qiu, F.G. Expedient construction of the Ziegler
intermediate useful for the synthesis of Forskolin via consecutive rearrange-
ments. Org. Lett., 2009, 11(23), 5442-5444.
[11] Corey, E.J.; Paul, D.S.J.; John, C. Total synthesis of (A)-Forskolin. J. Am.
Chem. Soc., 1988, 110(11), 3672-3673.
[12] Hack, D.; Chauhan, P.; Deckers, K.; Hermann, G. N.; Mertens, L.; Raabe,
G.; Enders, D. Combining silver catalysis and organocatalysis: A sequential
Michael addition/hydroalkoxylation one-pot approach to annulated coumar-
ins. Org. Lett., 2014, 16 (19), 5188-5191.
[13] Frederick, E.Z.; Burton, H.J.; Manohar, T.S. Asynthetic route to Forskolin. J.
Am. Chem. Soc., 1987, 109(26), 8115-8116.
[14] Hashimoto, S.; Sakata, S.; Sonegawa, M.; Ikegami, S. A total synthesis of
(±)-Forskolin. J. Am. Chem. Soc., 1988, 110(11), 3670-3672.
[15] Kashman, Y.; Gustafson, K.R.; Fuller, R.W.; Nd, C.J.; Mcmahon, J.B.;
Currens, M.J.; BuckheitJr., R.W.; Hughes, S.H.; Cragg, G.M.; Boyd M.R.
The calanolides, a novel HIV-inhibitory class of coumarin derivatives from
the tropical rainforest tree, Calophyllum lanigerum. J. Med. Chem., 1992,
35(15), 2735-2743.
[16] Tomohiro, T.; Takuya, K.; Tsutomu, I. Enantiose-lective total synthesis of
anti HIV-1 active (+)-calanolide A through a quinine-catalyzed a symmetric
intramolecular oxo-Michael addition. Tetrahedron Lett., 2000, 41(52),
10229-10232.
[17] Chandrasekhar, S.; Rambabu, C.H.; Shyamsunder, T. Total synthesis of
aculeatins A and B via a tethered oxa-Michael approach. Tetrahedron Lett.,
2007, 48(27), 4683-4685.
[18] Takasu, K.; Mizutani, S.; Noguchi, M.; Kei Makita, A.; Ihara, M. Total
synthesis of (±)-Culmorin and (±)-Longiborneol: An efficient construction of
tricyclo[6.3.0.03,9]undecan-10-one by intramolecular double Michael addi-
tion. J. Org. Chem., 2000, 65(13), 4112-4119.
[19] Fukushima, M.; Morii, A.; Hoshi, T.; Suzuki, T.; Hagiwara, H. Total synthe-
sis of Valeriananoids A, B, and C via autocatalytic diastereoselective domino
Michael reaction. Tetrahedron, 2007, 63(30), 7154-7164.
[20] Spande, T.F.; Garraffo, H.M.; Edwards, M.W.; Yeh, H.J.C.; Pannell, L.; &
Daly, J.W. Epibatidine: A novel (chloropyridyl)-azabicycloheptane with po-
tent analgesic activity from an ecuadoran poison frog. J. Am. Chem. Soc.,
1992, 114(9), 3475.
[21] Hoashiy, Y.T. Asymmetric synthesis of (-)-Epibatidine. Tetrahedron Lett.,
2004, 45(50), 9185-9188.
[22] Kayal, S.; Mukherjee, S. Catalytic asymmetric Michael addition/cyclization
cascade reaction of 3-isothiocyanatooxindoles with nitro olefins. Eur. J. Org.
Chem., 2014, 2014(30), 6696-6700.
[23] Huang, X.; Yi, W.B.; Ahad, D.; & Zhang, W. Recyclable cinchona alkaloid
catalyzed asymmetric michael addition reaction. Tetrahedron Lett., 2013,
54(45), 6064-6066.
[24] Muramulla, S.; Ma, J.A.; Zhao, C.G. Michael addition of ketones and alde-
hydes to maleimides catalyzed by modularly designed organocatalysts. Adv.
Synth. Catal., 2013, 355(7), 1260-1264.
[25] Tsakos, M.; Elsegood, M.R.J.; Kokotos, C.G. Organocatalytic asymmetric
domino Michael-Henry reaction for the synthesis of substituted bicy-
clo[3.2.1]octan-2-ones. Chem. Commun., 2013, 49, 2219-2221.
[26] Oueis, E.; Nachon, F.; Sabot, C.; & Renard, P.Y. First enzymatic hydroly-
sis/thio-Michael addition cascade route to synthesis of AChE inhibitors.
Chem. Commun., 2014, 50, 2043-2045.
[27] Chen, K.; Pullarkat, S.A. A tandem Heck-aza-Michael addition protocol for
the one-pot synthesis of isoindolines from unprotected amines. Org. Biomol.
Chem., 2012, 10, 6600-6606.
[28] Gu, K.Q. Organic Chemistry (Second Edition), Shanghai science and Tech-
nology Press, 1984, 138.
[29] Hua, W.T.; House H.O. The Modern Synthesis, Peking University press,
1985, 466-482.
[30] Huang, X. Organic Synthesis (I), Higher education press, 1992, 14.